This application is a division of U.S. Ser. No. 08/823,029, filed Mar. 21, 1997, which-in-turn claims the benefit of the filing of U.S. Provisional Application No. 60/014,157, filed Mar. 27, 1996, U.S. Provisional Application No. 60/030,536, filed Oct. 31, 1996 and U.S. Provisional Application No. 60/039,124, filed Feb. 25, 1997. This invention relates to novel compounds and pharmaceutical compositions, and to methods of using same in the treatment of psychiatric disorders and neurological diseases including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders.
Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC)-derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J.E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].
Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer""s disease, Parkinson""s disease, Huntington""s disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)].
In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].
There has also been a role postulated for CRF in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist a-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the xe2x80x9canxiogenicxe2x80x9d effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].
The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (a-helical CRF9-41) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p221 (1990)].
DuPont Merck PCT application US94/11050 describes corticotropin releasing factor antagonist compounds of the formula: 
and their use to treat psychiatric disorders and neurological diseases. Included in the description are fused pyridines and pyrimidines of the formula: 
Where:
V is CR1a or N; Z is CR2 or N; A is CR30 or N;
and D is CR28 or N.
Pfizer WO 95/33750 describes corticotropin releasing factor antagonist compounds useful in the treatment of CNS and stress disorders. The description includes compounds of the formulae: 
where A is CR7 or N; B is xe2x80x94NR1R2; R1 is substituted or unsubstituted alkyl; R2 is substituted or unsubstituted alkyl, aryl or heteroaryl; R3 is methyl, halo, cyano, methoxy, etc.; R4 is H, substituted or unsubstituted alkyl, halo, amino, nitro, etc.; R5 is substituted or unsubstituted aryl or heteroaryl; R6 is H or substituted or unsubstituted alkyl; R7 is H, methyl, halo, cyano, etc.; R16 and R17 taken together form an oxo (xe2x95x900) group; and G is xe2x95x900, xe2x95x90S, xe2x95x90NH, xe2x95x90NCH3, hydrogen, methyl, methoxy, etc. Pfizer WO 95/33750 also describes intermediates of the formula: 
where A can be N, D can be OH, R4 can be nitro, R19 is methyl or ethyl, Z can be NH or N(CH3), and R5 is substituted phenyl or substituted pyridyl, each substituted with 2 or 3 substituents selected from C1-C4 alkyl, chloro and bromo.
Pfizer WO 95/34563 describes corticotropin releasing factor antagonist compounds, including compounds of the formula: 
where A, B and the R groups have definitions similar to those in WO 95/33750.
Pfizer WO 95/33727 describes corticotropin releasing factor antagonist compounds of the formula: 
where A is CH2 and Z can be a heteroaryl moiety.
Ganguly et al., U.S. Pat. No. 4,076,711 describes triazolo[4,5-d]pyrimidines of the formula: 
where X is halo, xe2x80x94NR1R or alkoxy, with R1 and R each being H or alkyl; Y is alkyl, cycloalkyl, hydroxycycloalkyl, phenyl, bicycloalkyl or phenylalkyl or bicycloalkylalkyl; and Q is H or Y. The patent states that the compounds are useful in the treatment of psoriasis.
Tanji et al., Chem. Pharm. Bull. 39(11)3037-3040 (1991), describes triazolo[4,5-d]pyrimidines of the formula: 
where halo is I, Br or Cl, Ph is phenyl and Me is methyl. No utility for the compounds is described.
Settimo et al., Il Farmaco, Ed. Sc., 35 (4), 308-323 (1980) describes 8-azaadenines (triazolo[4,5-d] pyrimidines) of the formula: 
where R1 is H or benzyl and R2 is p-methylphenyl.
Biagi et al., Il Farmaco, 49 (3), 183-186, (1994), describes N(6)-substituted 2-n-butyl-9-benzyl-8-azaadenines of the formula: 
where R2 can be alkyl, phenyl, or benzyl. The paper states that the compounds have affinity for adenosine receptors.
Thompson et al., J. Med. Chem., 1991, 34, 2877-2882, describes N6,9-disubstituted adenines of the formula: 
where Ph is phenyl or (when C-2 is unsubstituted) 2-fluorophenyl. The paper states that the compounds have selective affinity for the A1 adenosine receptor.
Kelley et al., J. Med. Chem. 1990, 31, 606-612, describes the compound 
where R6 is NHC6H5 and R9 is CH2C6H5, and reports that the compound was inactive when tested for anticonvulsant activity. The paper reports that various 6-(alkylamino)-9-benzyl-9H-purine analogs of the above compound exhibited anticonvulsant activity.
Kelley et al., J. Med. Chem. 1990, 33, 1360-1363, describes 6-anilino-9-benzyl-2-choro-9H-purines of the formula: 
where Bz is benzyl or (when R4 is H) p-methylbenzyl and R4 is H or alkyl, alkoxy, halo, cyano, nitro, etc. Tests of the compounds for antirhinoviral activity are reported.
Kelley et al., J. Heterocyclic Chem., 28, 1099 (1991), describes 6-substituted-9-(3-formamidobenzyl)-9H-purines of the formula: 
where R1 is NH2 or NHCHO. The compound where R1 is NHCHO was tested for benzodiazepine receptor binding and was inactive, although various analogs were active.
Khairy et al., J. Heterocyclic Chem., 22, 853 (1985), describes synthesis of certain 9-aryl-9H-purin-6-amines of the formula: 
where the R groups are H, methyl, ethyl, isopropyl, chloro or fluoro.
This invention is a class of novel compounds which are CRF receptor antagonists and which can be represented by formula I or formula II: 
or a pharmaceutically acceptable salt or pro-drug form thereof, wherein:
X is N or CR1;
Y is N or CR2;
Z is NR3, O, or S(O)n;
G is O or S;
Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl or pyrazolyl, each optionally substituted with 1 to 5 R5 groups;
R1 is independently at each occurrence H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halo, CN, C1-C4 haloalkyl, xe2x80x94NR9R10, NR9COR10, xe2x80x94OR11, SH or xe2x80x94S(O)nR12;
R2 is H, C1-C4 alkyl, C1-C6 cycloalkyl, halo, CN, xe2x80x94NR6R7, NR9COR10, C1-C4 haloalkyl, xe2x80x94OR7, SH or xe2x80x94S(O)nR12;
R3 is H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl or C4-C12 cycloalkylalkyl each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, xe2x80x94OR7, SH, xe2x80x94S(O)nR13, xe2x80x94COR7, xe2x80x94CO2R7, xe2x80x94OC(O)R13, xe2x80x94NR8COR7, xe2x80x94N(COR7)2, xe2x80x94NR8CONR6R7, xe2x80x94NR8CO2R13, xe2x80x94NR6R7, xe2x80x94CONR6R7, aryl, heteroaryl and heterocyclyl, where the aryl, heteroaryl or heterocyclyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, xe2x80x94OR7, SH, xe2x80x94S(O)nR13, xe2x80x94COR7, -CO2R7, xe2x80x94OC(O)R13, xe2x80x94NR8COR7, xe2x80x94N(COR7)2, xe2x80x94NR8CONR6R7, xe2x80x94NR8CO2R13, xe2x80x94NR6R7, and xe2x80x94CONR6R7;
R4 is H, C1-C4 alkyl, allyl, or propargyl, where C1-C4 alkyl, allyl, or propargyl is optionally substituted with C3-C6 cycloalkyl and where C1-C4 alkyl is optionally substituted with, xe2x80x94OR7, xe2x80x94S(O)nR12 or xe2x80x94CO2R7;
R5 is independently at each occurrence C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, xe2x80x94NO2, halo, xe2x80x94CN, C1-C4 haloalkyl, xe2x80x94NR6R7, NR8COR7, NR8CO2R7, xe2x80x94COR7 xe2x80x94OR7, xe2x80x94CONR6R7, xe2x80x94CO(NOR9)R7, CO2R7, or xe2x80x94S(O)nR7, where C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl and C4-C12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, xe2x80x94NO2, halo, xe2x80x94CN, xe2x80x94NR6R7, xe2x80x94NR6R7, NR8COR7, NR8CO2R7, xe2x80x94COR7 xe2x80x94OR7, xe2x80x94CONR6R7, CO2R7, xe2x80x94CO(NOR9)R7, or xe2x80x94S(O)nR7;
R6 and R7 are independently at each occurrence H, C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl)-, heteroaryl or heteroaryl(C1-C4 alkyl)-; or NR6R7 is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine;
R8 is independently at each occurrence H or C1-C4 alkyl;
R9 and R10 are independently at each occurrence selected from H, C1-C4 alkyl, or C3-C6 cycloalkyl;
R11 is H, C1-C4 alkyl, C1-C4 haloalkyl, or C3-C6 cycloalkyl;
R12 is C1-C4 alkyl or C1-C4 haloalkyl;
R13 is C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl)-, heteroaryl or heteroaryl(C1-C4 alkyl)-;
aryl is phenyl or naphthyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, xe2x80x94OR7, SH, xe2x80x94S(O)nR13, xe2x80x94COR7, xe2x80x94CO2R7, xe2x80x94OC(O)R13, xe2x80x94NR8COR7, xe2x80x94N(COR7)2, xe2x80x94NR8CONR6R7, xe2x80x94NR8CO2R13, xe2x80x94NR6R7, and xe2x80x94CONR6R7;
heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl , pyrazolyl, triazolyl, tetrazolyl, or indazolyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1xe2x80x94C4 haloalkyl, cyano, xe2x80x94OR7, SH, xe2x80x94S(O)nR13, xe2x80x94COR7, xe2x80x94CO2R7, xe2x80x94OC(O)R13, xe2x80x94NR8COR7, xe2x80x94N(COR7)2, xe2x80x94NR8CONR6R7, xe2x80x94NR8CO2R13, xe2x80x94NR6R7, and xe2x80x94CONR6R7;
heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, xe2x80x94OR7, SH, xe2x80x94S(O)nR13, xe2x80x94COR7, xe2x80x94CO2R7, xe2x80x94OC(O)R13, xe2x80x94NR8COR7, xe2x80x94N(COR7)2, xe2x80x94NR8CONR6R7, xe2x80x94NR8CO2R13, xe2x80x94NR6R7, and xe2x80x94CONR6R7;
n is independently at each occurrence 0, 1 or 2;
provided that R4 in formula I is not H:
(a) when X is N, Y is N, Z is NR3, R1 is H, R3 is
H or benzyl, and Ar is p-methylphenyl;
(b) when X is N, Y is N, Z is NR3, R1 is butyl,
R3 is benzyl, and Ar is phenyl;
(c) when X is N, Y is CH, Z is NR3, R3 is methyl,
R1 is H, and Ar is phenyl or 2-fluorophenyl;
(d) when X is N, Y is CH, Z is NR3, R3 is methyl,
R1 is Cl and Ar is phenyl;
(e) when X is N, Y is CH, Z is NR3, R1 is Cl, R3 
is benzyl, and Ar is phenyl or substituted phenyl;
(f) when X is N, Y is CH, Z is NR3, R3 is p-methylbenzyl, and Ar is phenyl;
(g) when X is N, Y is CR2, Z is NR3, R2 is CH3,
R3 is H, and Ar is phenyl or phenyl substituted with methyl, ethyl, isopropyl, fluoro or chloro;
(h) when X is N, Y is N, Z is NR3, R3 is cyclopropylmethyl, R1 is H, and Ar is 2-bromo-4-isopropylphenyl, or
(i) when X is N, Y is N, Z is S, R1 is H, and Ar is 2-bromo-4-isopropylphenyl.
Preferred compounds of this invention are compounds of formula I and formula II and pharmaceutically acceptable salts and pro-drug forms thereof, wherein, independently or concurrently:
X is N or CR1;
Y is N or CR2;
Z is NR3, O, or S(O)n;
G is O or S;
Ar is phenyl or pyridyl, each optionally substituted with 1 to 3 R5 groups;
R1 is independently at each occurrence H, C1-C4 alkyl, halo, CN, C1-C4 haloalkyl, xe2x80x94NR9R10, xe2x80x94OR11 or xe2x80x94S(O)nR12;
R2 is H, C1-C4 alkyl, C1-C6 cycloalkyl, halo, CN, xe2x80x94NR6R7, NR9COR10, C1-C4 haloalkyl, xe2x80x94OR7 or xe2x80x94S(O)nR12;
R3 is H, C1-C10 alkyl, C2-C10 alkenyl, c2-c10 alkynyl, C3-C8 cycloalkyl or C4-C12 cycloalkylalkyl each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, xe2x80x94OR7, xe2x80x94S(O)nR13, xe2x80x94CO2R7, xe2x80x94NR8COR7, xe2x80x94NR8CONR6R7, xe2x80x94NR8CO2R13, xe2x80x94NR6R7, aryl and heteroaryl, where the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, halo, cyano, xe2x80x94OR7, xe2x80x94S(O)nR7, xe2x80x94CO2R7, xe2x80x94NR8COR7, xe2x80x94NR8CONR6R7, xe2x80x94NR8CO2R7and xe2x80x94NR6R7;
R4 is H, C1-C4 alkyl, allyl, or propargyl;
R5 is independently at each occurrence C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, xe2x80x94NO2, halo, xe2x80x94CN C1-C4 haloalkyl, xe2x80x94NR6R7, COR7 xe2x80x94OR7, xe2x80x94CONR6R7, xe2x80x94CO(NOR9)R7, CO2R7, or xe2x80x94S(O)nR7, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C4-C12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, xe2x80x94NO2, halo, xe2x80x94CN, xe2x80x94NR6R7, COR7, xe2x80x94OR7, xe2x80x94CONR6R7, CO2R7, xe2x80x94CO(NOR9)R7, or xe2x80x94S(O)nR7;
R6 and R7 are independently at each occurrence H, C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl)-, heteroaryl or heteroaryl(C1-C4 alkyl)-; or NR6R7 is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine;
R8 is independently at each occurrence H or C1-C4 alkyl;
R9 and R10 are independently at each occurrence selected from H, C1-C4 alkyl, or C3-C6 cycloalkyl;
R11 is H, C1-C4 alkyl, C1-C4 haloalkyl, or C3-C6 cycloalkyl;
R12 is C1-C4 alkyl or C1-C4 haloalkyl;
R13 C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl)-, heteroaryl or heteroaryl(C1-C4 alkyl)-;
aryl is phenyl or naphthyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, halo, cyano, xe2x80x94OR7, xe2x80x94S(O)nR12, xe2x80x94C02R8, xe2x80x94NR8COR7, xe2x80x94NR8CONR6R7, xe2x80x94NR8C2R12, and -NR6R7;
heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, or indazolyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, halo, cyano, xe2x80x94OR7, xe2x80x94S(O)nR12, xe2x80x94CO2R8, xe2x80x94NR8COR7, xe2x80x94NR8CONR6R7, xe2x80x94NR8CO2R12, and xe2x80x94NR6R7;
n is independently at each occurrence 0, 1 or 2.
Of the preferred compounds, more preferred are those of formula I wherein Z is NR3 and pharmaceutically acceptable salts and pro-drug forms thereof.
Included in this invention is the method of treating affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer""s disease, gastrointestinal disease, anorexia nervosa or other feeding disorder, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorder, or fertility problem in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula I or II.
Also included in this invention are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of any one of the above-described compounds.
This invention also includes intermediate compounds useful in preparation of the CRF antagonist compounds and processes for making those intermediates, as described in the following description and claims.
The CRF antagonist compounds provided by this invention (and especially labelled compounds of this invention) are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF receptor.
Many compounds of this invention have one or more asymmetric centers or planes. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are included in the present invention. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. The compounds may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
The term xe2x80x9calkylxe2x80x9d includes both branched and straight-chain alkyl having the specified number of carbon atoms. xe2x80x9cAlkenylxe2x80x9d includes hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. xe2x80x9cAlkynylxe2x80x9d includes hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain alkyl having the specified number of carbon atoms, substituted with 1 or more halogen; xe2x80x9calkoxyxe2x80x9d represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; xe2x80x9ccycloalkylxe2x80x9d is intended to include saturated ring groups, including mono-, bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth. xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d includes fluoro, chloro, bromo, and iodo.
The term xe2x80x9csubstitutedxe2x80x9d, as used herein, means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By xe2x80x9cstable compoundxe2x80x9d or xe2x80x9cstable structurexe2x80x9d is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term xe2x80x9cappropriate amino acid protecting groupxe2x80x9d means any group known in the art of organic synthesis for the protection of amine or carboxylic acid groups. Such amine protecting groups include those listed in Greene and Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d John Wiley and Sons, New York (1991) and xe2x80x9cThe Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Any amine protecting group known in the art can be used. Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl.
The term xe2x80x9camino acidxe2x80x9d as used herein means an organic compound containing both a basic amino group and an acidic carboxyl group. Included within this term are natural amino acids, modified and unusual amino acids, as well as amino acids which are known to occur biologically in free or combined form but usually do not occur in proteins. Included within this term are modified and unusual amino acids, such as those disclosed in, for example, Roberts and Vellaccio (1983) The Peptides, 5: 342-429, the teaching of which is hereby incorporated by reference. Modified or unusual amino acids which can be used to practice the invention include, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, an N-Cbz-protected amino acid, ornithine, 2,4-diaminobutyric acid, homoarginine, norleucine, N-methylaminobutyric acid, naphthylalanine, phenylglycine, xcex2-phenylproline, tert-leucine, 4-aminocyclohexylalanine, N-methyl-norleucine, 3,4-dehydroproline, N,N-dimethylaminoglycine, N-methylaminoglycine, 4-aminopiperidine-4-carboxylic acid, 6-aminocaproic acid, trans-4-(aminomethyl)-cyclohexanecarboxylic acid, 2-, 3-, and 4-(aminomethyl)-benzoic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclopropanecarboxylic acid, and 2-benzyl-5-aminopentanoic acid.
The term xe2x80x9camino acid residuexe2x80x9d as used herein means that portion of an amino acid (as defined herein) that is present in a peptide.
The term xe2x80x9cpeptidexe2x80x9d as used herein means a compound that consists of two or more amino acids (as defined herein) that are linked by means of a peptide bond. The term xe2x80x9cpeptidexe2x80x9d also includes compounds containing both peptide and non-peptide components, such as pseudopeptide or peptide mimetic residues or other non-amino acid components. Such a compound containing both peptide and non-peptide components may also be referred to as a xe2x80x9cpeptide analogxe2x80x9d.
The term xe2x80x9cpeptide bondxe2x80x9d means a covalent amide linkage formed by loss of a molecule of water between the carboxyl group of one amino acid and the amino group of a second amino acid.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d includes acid or base salts of the compounds of formulas (I) and (II). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
Pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d are considered to be any covalently bonded carriers which release the active parent drug of formula (I) or (II) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of formula (I) and (II) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formulas (I) and (II); and the like.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d of a compound of this invention means an amount effective to antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety or depression in a host.
The bicylic fused pyrimidine and pyridines of this invention can be prepared by one of the general schemes outlined below (Scheme 1-9).
Compounds of the Formula (I) wherein X=Y=N and Z=NR3, can be prepared as shown in Scheme 1. 
wherein Xxe2x95x90Yxe2x95x90N; Zxe2x95x90NR3 
The 4,6-dihydroxypyrimidines (III) can be nitrated using fuming nitric acid and then converted into intermediates (IV) by the action of phosphorous oxychloride with the optional assistance of a catalyst such as dialkylanilines (see: Brown, D. J. et.al. J. Chem. Soc., 1954, 3832). The amino group of pyrimidines of Formula (V) can be prepared from the corresponding nitro compounds (IV) by treatment with reducing agents such as, but not limited to, sodium dithionate, iron or zinc, or catalytic hydrogenation (see: Larock, R. C. Comprehensive Organic Transformations, VCH Publishers, New York, 1989, 411). Reaction with Arxe2x80x94NH2 can be used to provide compounds of Formula (VI). Conditions which may facilitate this transformation include the optional presence of protic or aprotic acids, or bases such as alkali metal hydrides, trialkylamines, or alkali metal carbonates, or alkali metal bis(trimethylsilyl)amides wherein the metal can be sodium, lithium, or potassium. These reactions may be conducted neat, or in the optional presence of solvents such as but not limited to cyclic ethers such as tetrahydrofuran, dialkylformamides, ethylene glycol, 2-ethoxyethanol, halocarbons, alkanenitriles, or alkyl alcohols at room temperature or at elevated temperature up to the boiling point of the solvent employed. One skilled in the art of organic synthesis will readily understand the optimal combinations of these conversions to prepare a number of compounds of Formula (VI). Cyclization to triazolopyrimidines of Formula (VII) can then be readily accomplished by diazotization and cyclization of the diamino compounds of Formula (VI) with an alkali metal nitrite in the presence of acid in water with or without an organic cosolvent such as halocarbons, or cyclic ethers. Treatment of compound of Formula (VII) with primary amines then can provide the intermediates (VIII) using reaction conditions similar to those employed for the conversion of (V) to (VI). The rearranged triazolopyrimidine of Formula (IX) may be obtained from the triazolopyrimidine of Formula (VIII) by treatment with base such as but not limited to, alkali metal hydrides, alkaline earth metal hydrides, alkali metal dialkyl amides in inert solvents such as dialkylformamides, dialkylacetamides at temperatures ranging from 0xc2x0 to 200xc2x0 C. Finally, reaction with an appropriate R4L wherein L is a suitable leaving group such as halo, methanesulfonate, p-toluenesulfonate, or triflate in the presence or absence of bases such as but not limited to, alkali metal hydrides, alkaline earth metal hydrides, alkali metal dialkyl amides in inert solvents such as dialkylformamides or dialkylacetamides at temperatures ranging from 0xc2x0 to 200xc2x0 C. can be used to generate compounds of Formula (I).
Alternatively, compounds of Formula (I) wherein X=Y=N and Z=NR3, of this invention can be prepared as outlined in Scheme 2: 
wherein X=Y=N, Z=NR 3 
Treatment of compound of Formula (V) with primary amines can provide the diamino substituted pyrimidines (X). Conditions which facilitate this transformation are detailed previously for the conversion of (VII) to (VIII). Cyclization to triazolopyrimidines of Formula (XI) can then be readily accomplished by following the conditions already described for the conversion of (VI) to (VII) in Scheme 1. The leaving group such as, but not limited to, halogen can then be displaced by addition of Arxe2x80x94NH2 to provide compounds of Formula (IX) by utilizing the conditions described for the conversion of (V) to (VI). Compounds of Formula (IX) can be converted to (I) in the same way as outlined in Scheme 1.
Compounds of the Formula (VI) can also prepared by an another approach (Scheme 3) involving addition of Arxe2x80x94NH2 to (IV) to afford compounds of Formula (XII). 
The nitro group in (XII) can be reduced to give compounds of Formula (VI) under conditions similar to those described for the transformation of (IV) to (V) in Scheme 1. Alternatively, as shown in Scheme 3, addition of Arxe2x80x94NH2 to compounds of Formula (IV) can generate in-situ the pyrimidones (XIII). For example, treatment of dichloropyrimidines of Formula (IV) with one equivalent of Arxe2x80x94NH2 in the presence of solvents such as (but not limited to) dialkylsulfoxides, dialkylformamides, and alkyl alcohols readily generate pyrimidones (XIII). Compounds of Formula (XIII) can be converted into (IV) by the action of phosphorous oxychloride with the optional assistance of a catalyst such as dialkylanilines with or without an inert solvent. Compounds of Formula (VI) are elaborated to structures of Formula (I) as previously shown in Scheme 1.
Scheme 4 outlines another route to fused triazolopyrimidine type of compounds of this invention. 
wherein X=Y=N; Z=NR3 
4,6-dihydroxy-5-nitropyrimidines can be treated with aryl sulfonic anhydrides, aryl sulfonyl chlorides, alkyl sulfonic anhydrides or alkyl sulfonyl chlorides in the presence or absence of bases such as alkali metal hydrides, alkaline earth metal hydrides, alkali metal dialkyl amides in inert solvents such as dialkylformamides, dialkylacetamides at temperatures ranging from 0xc2x0 to 200xc2x0 C. to give intermediates of Formula (XIV). Compounds of Formula (XIV) are treated with primary amines to give aminonitropyrimidines (XV). Treatment of (XV) with Arxe2x80x94NH2 can provide compounds of Formula (XVI). Compounds of the formula (XVI) can be reduced to amino derivatives (XVII) using the reagents described for the conversion of (IV) to (V) in Scheme 1. Intermediate (XVII) can be converted to a mixture of (VIII) and (IX) by diazotization and cyclization. Compounds of the Formula (VIII) can be converted to (IX) by treatment with base such as but not limited to, alkali metal hydrides, alkaline earth metal hydrides, alkali metal dialkyl amides in an inert solvent. Compounds of Formula (IX) are elaborated to give (I) as delineated in Scheme 1.
Fused imidazolopyrimidines of the Formula (I) wherein X=N, Y=CR2, and Z=NR3, can be prepared from compound (X) as shown in Scheme 5. 
wherein X=N, Y=CR2, Z=NR3 
Treatment of (X) with an acylating agent such as, but not limited to, alkyl anhydrides, haloalkyl anhydrides, alkylamides, haloalkyl amides, trialkylorthoesters R2(OR)3 (where R is C1-C4 alkyl), guanidines, cyanogen bromide, R2COOH, urea or thiourea in the presence or absence of an acid (such as HOAc, HCl, H2SO4) in the presence or absence of an organic cosolvent such as alkyl alcohols, cyclic ethers, or aromatic solvents at temperatures ranging from 0xc2x0 to 200xc2x0 C. Treatment of (XVIII) with Arxe2x80x94NH2 can provide compounds of Formula (XIX). Finally, alkylation of compound (XIX) can provide imidazolopyrimidine (I, wherein X=N, Y=CR2, Z=NR3).
The 1,2,3-thiadiazolo[5,4-d]pyrimidines of the formula (I) (wherein X=Y=N and Z=S), can be prepared as shown in Scheme 6. 
Compounds of the formula (VII) with thiourea can react upon heating in presence of solvents such as but not limited to, cyclic ethers such as tetrahydrofuran, dialkylformamides such as dimethylformamide, dialkyl acetamides, ethylene glycol, 2-ethoxyethanol, halocarbons such as methylene chloride, alkanenitriles such as acetonitrile, or alkyl alcohols such as methanol, ethanol to give compound (XX) which is alkylated to afford thiadiazolpyrimidine (I) (wherein X=Y=N and Z=S). Compounds of Formula (I) can be converted to sulfoxides as well sulfones under a variety of oxidizing agents such as but not limited to, NaIO4, KMnO4 or m-chloroperbenzoic acid.
The method of synthesis of the triazolopyridines of this invention is shown in Scheme 7. 
The hydroxy groups in (XXI) can be converted into chloro groups by the action of phosphorous oxychloride with the optional assistance of a catalyst such as dialkylaniline (see: Brown, D. J. et.al. J. Chem. Soc., 1954, 3832) to afford compounds of Formula (XXII). Addition of primary amines to compound (XXII) can provide alkylaminonitropyridines (XXIII). The nitro group in (XXIII) can be reduced using the conditions employed for the transformation of (IV) to (V) to give (XXIV). Diazotization and cyclization of (XXIV) can provide chlorotriazolopyridine derivatives (XXV) as was described for the conversion of (VI) to (VII) in Scheme 1. The chloro group can then be displaced by addition of Arxe2x80x94NH2 to afford compounds (XXVI) and then treated with R4L to give (I).
Imidazolopyridines of the present invention can be prepared from compound (XXIV) as shown in Scheme 7 by following the conditions outlined for the conversion of (X) to (XVIII) in Scheme 5. Treatment of compound (XXVII) with Arxe2x80x94NH2 using the conditions outlined in Scheme 1 can provide compounds of Formula (I, where R4=H). Alkylation with R4L can afford imidazolopyridines of formula I (where R4 is not equal to H).
Alternatively, the triazolopyridines can be synthesized as shown in Scheme 8. 
Treatment of compounds of Formula (XXI) with an aliphatic or aromatic amine in the appropriate organic solvent but not limited to, alkyl alcohols such as methanol, ethanol, propanol, butanol, alkyl alkanoates such as ethyl acetate, alkanenitriles such as acetonitrile, dialkyl formamides such as DMF gives the corresponding ammonium salt, which upon treatment with POCl3 at temperatures from 25 to 120xc2x0 C., give compounds of Formula (XXVIII). Treatment of compounds of Formula (XXVIII) with appropriate primary amines in an organic solvent such as but not limited to, alkyl alcohols such as methanol, ethanol, propanol, butanol, alkyl alkanoates such as ethyl acetate, alkanenitriles such as acetonitrile, dialkyl formamides such as DMF, dialkylsulfoxides at temperatures from 25 to 120xc2x0 C. to give (XXIX). This was converted to (XXIII) by treatment with POCl3 at temperatures from 25 to 120xc2x0 C. Compounds of Formula (XXIII) could be coupled with Arxe2x80x94NH2 with or without the presence of solvent at temperatures from 25 to 200xc2x0 C. to give product (XXX). These could be converted to intermediates (XXXI) by reduction of the nitro group under a variety of reducing conditions, such as those used for the conversion of (IV) to (V) in Scheme 1. The final cyclizaton was carried out as described for the conversion of (VI) to (VII) in Scheme 1.
Compounds of general formula (II) may be prepared according to the procedures outlined in Scheme 9. 
Intermediates of formula (X), (XV) or (XXIV) may be converted to compounds of formula (XXXIII) by treatment with an acylating agent in the presence or absence of a base in an inert solvent at reaction temperatures ranging from xe2x88x9278xc2x0 C. to 200xc2x0 C. Acylating agents include, but are not limited to, phosgene, thiophosgene, diphosgene, triphosgene, carbonyl diimidazole, thiocarbonyl diimidazole, dialkylcarbonates (such as diethyl carbonate) or RaRbN(Cxe2x95x90G)ORc (where G=O, S; Ra, Rb, and Rc are independently C1-C8 alkyl). Bases include, but are not limited to, alkali metal alkoxides, akali metal hydrides, trialkyl amines, pyridine, 4-dimethylaminopyridine, alkali metal dialkyl amides or alkali metal bis(trimethylsilyl)amides. Inert solvents include, but are not limited to, halocarbons, alkanenitriles, dialkylformamides, dialkylacetamides, dialkyl ethers, cyclic ethers such as tetrahydrofuran or dioxane, or alkyl alcohols. Intermediates of (XXXIII) may be converted to compounds of formula (XXXIV) (Formula (II) where R4=H) by reaction with ArNH2, using the conditions described for the conversion of compound (V) to (VI) in Scheme 1.
Compounds of Formula (XXXV) may be prepared from compounds of structure (XXXIII) by reaction with R13L (where L is a leaving group such as halide, alkanesulfonate or arylsulfonate) in the presence or absence of a base in an inert solvent. Bases and inert solvents may be the same as those listed above for the preparation of (XXXIII). Intermediates of Formula (XXXV) can be reacted with ArNH2 to give compounds of formula (XXXVI) (Formula (II), where R4=H) using the conditions described for the conversion of compound (V) to (VI) in Scheme 1. Compounds of Formula (XXXVI) may be converted to compounds of (XXXVII) (Formula (II), where R4 does not equal H) by treatment with R4L (where L is a leaving group such as halide, alkanesulfonate or arylsulfonate) in the presence or absence of a base in an inert solvent. Bases and inert solvents may be the same as those listed above for the preparation of (XXXIII).
As illustrated in Scheme 10, treatment of compounds of Formula (XXI) with an aliphatic or aromatic amine in an appropriate organic solvent (such as but not limited to, alkyl alcohols such as methanol, ethanol, propanol, butanol, alkyl alkanoates such as ethyl acetate, alkanenitriles such as acetonitrile, dialkyl formamides such as DMF) gives the corresponding ammonium salt, which upon treatment with POCl3 at temperatures from 25 to 120xc2x0 C., give compounds of Formula (XXVIII). Treatment of compounds of Formula (XXVIII) with appropriate primary amines R3NH2 in an organic solvent (such as but not limited to, alkyl alcohols such as methanol, ethanol, propanol, butanol, alkyl alkanoates such as ethyl acetate, alkanenitriles such as acetonitrile, dialkyl formamides such as DMF, dialkylsulfoxides) at temperatures from 25 to 120xc2x0 C. provides compounds of Formula (XXIX). These can be converted to (XXIII) by treatment with POCl3 at temperatures from 25 to 120xc2x0 C. Compounds of Formula (XXIII) can be converted to intermediates (XXIV) by reduction of the nitro group under a variety of reducing conditions, such as those used for the conversion of (IV) to (V) in Scheme 1. Diazotization and cyclization of (XXIV) can provide chlorotriazolopyridine (XXV) as was described for the conversion of of (VI) to (VII) in Scheme I. The chloro group can then be displaced by addition of Arxe2x80x94NH2 in the presence of an acid such as but not limited to HCl, H2SO4, AcOH, methanesulfonic acid, p-toluenesulfonic acid in inert solvents such as toluene, xylenes at temperatures ranging from 0xc2x0 to 200xc2x0 C. to afford product I. Salts of I are prepared by combining the free base with appropriate acid in a suitable organic solvent. 
wherein X=CR1, Y=N, Z=NR3 
As shown in Scheme 11, reaction of a 4-amino-3-nitro-pyridone of formula (XXIX) with a reducing agent, such as Na2S2O4 affords the corresponding 4-amino-3-amino-pyridone of formula (XXXVII). This transformation can be effected under a variety of reducing conditions, such as catalytic hydrogenation, reducing metal reaction (Fe, Sn, Zn), hydride reaction (NaBH4, LiAlH4) etc., which are known to those skilled in the art. The 4-amino-3-amino-pyridone can be converted to the triazolopyridone of formula (XXXVIII) by treatment with an alkali metal nitrite, such as NaNO2, under acidic conditions. The resulting triazolopyridone can be converted to the corresponding halo-triazolopyridine of formula (XXXIX)(X=Cl, Br), by treatment with a halogenating agent such as POCl3, PBr3, POBr3. Alternatively X can be an appropriate leaving group resulting from treatment of the triazolopyridone with triflic, tosic or mesyl anhydride in the presence of a base. The triazolopyridine can be coupled with arylamines ArNH2 under acidic, basic or thermal catalysis to compounds of Formula I. 